In the past year we have been involved in an effort to define additional risk loci for Alzheimer's disease and to understand the mechanistic basis of these associations. This has involved being a contributor to the reanalysis of large tracts of genome wide association data and much of this work, which identifies several new loci, and a converging molecular pathway, has been published. We have expanded this work to characterize the extent of genetic variability at the CLU and PICALM loci, across different Alzheimer's disease populations and in addition to examine the effects of certain Alzheimer's disease risk genotypes on readouts such as brain function via imaging. In this respect our efforts have used the reference data generated within our laboratory that facilitates testing association between candidate variants and gene expression and/or proximal DNA methylation. In addition, we are currently working with collaborators at UCL to perform exome sequencing on families and individuals with Alzheimer's disease;this work aims to identify moderate- to high-risk variants associated with disease.